Our understanding of genetic mechanisms controlling the evolution, formation, and pathological disruption of human neuronal circuits is impeded by a lack of comprehensive data on the developing brain transcriptome. The main goal of the two interrelated Grand Opportunity applications is to conduct a spatiotemporally comprehensive survey of the human brain transcriptome and create a unique multimodal atlas encompassing all pre- and postnatal developmental stages, including adolescence and adulthood. To achieve this ambitious goal in two years, we propose to bring together expertise in human and non-human primate brain development, large-scale transcriptional profiling, industrial scale histological data and atlas generation, MRI and DTI imaging, and the resources of the Allen Institute for Brain Science and Yale University in bioinformatics and information technology. This consortium will work together to create a series of large-scale data sets that will be integrated through a powerful public access web-based portal for visualizing, searching and sophisticated mining of spatiotemporal gene expression patterns in the anatomical context of human brain development. Specifically, the research planned to take place at Yale University will use high-throughput massively parallel RNA-sequencing (RNA-seq) methodology to gain a sensitive, specific and comprehensive view of the developing transcriptome across multiple regions of the human brain. We will analyze the whole transcriptome in up to 15 cerebral cortical and subcortical regions from both left and right sides of normal postmortem female and male brains at 12 stages of pre- and postnatal development. RNA-seq will provide a unique resource for comprehensive mining and functional analysis of the whole transcriptome. Expert- annotated MRI/DTI and reference atlases generated by the Allen Institute for Brain Science will provide the anatomical backbone of the resource, and the framework for informatics-based statistical analysis and generation of search and mining capabilities. Finally, direct links will be made to other non-human primate and rodent transcriptomes and cellular-level gene expression data sets available in participating laboratories to allow cross-species comparative analyses, both through web-based linking and parallel analysis of orthologous gene sets. The generated data will be available to the research community at-large via a user-friendly, web-based informatics framework. The expected results of the proposed studies will have a transformative effect on the field by cataloguing variations in gene regulation and alternative splicing across brain regions and developmental time-points for all coding and non-coding transcripts, enabling a better understanding of how specific susceptibility genes affect human brain development and potentially contribute to psychiatric disorders. PUBLIC HEALTH RELEVANCE: The identification of genes involved in formation and maturation of the human brain as outlined in this proposal will help in understanding normal human brain development and plasticity as well as the neurobiological foundations of mental disorders such as schizophrenia and autism. This research may further facilitate the identification of disease genes and the development of new therapeutic strategies for the treatment of these disorders.